Novel and reported variants in Parkinson's disease genes confer high disease burden among Indians. (September 2020)

• Record Type: Journal Article
• Authors: Kumar, Sumeet; Yadav, Navneesh; Pandey, Sanjay; Muthane, Uday B.; Govindappa, Shyla T.; Abbas, Masoom M.; Behari, Madhuri; Thelma, B.K.
• Is Part Of: Parkinsonism & related disorders. Volume 78(2020)
• Page Start: 46
• Page End: 52
• Publication Date: 2020-09
• Subjects: Parkinson's disease -- Indian population -- Rare variant burden -- Novel variants; Parkinson's disease -- Periodicals; Movement disorders -- Periodicals; Movement Disorders -- Periodicals; Nerve Degeneration -- Periodicals; Nervous System Diseases -- Periodicals; Parkinson Disease -- Periodicals; Tremor -- Periodicals; Parkinson, Maladie de -- Périodiques; Parkinson's disease; 616.833
• DOI: 10.1016/j.parkreldis.2020.07.014
• Languages: English
• ISSNs: 1353-8020

Abstract

Abstract: Background: Genetic heterogeneity in Parkinson's disease (PD) has been unambiguously reported across different populations. Assuming a higher genetic load, we tested variant burden in PD genes to an early onset PD cohort from India. Methods: Whole exome sequencing was performed in 250 PD patients recruited following MDS-UPDRS criteria. The number of rare variants in the 20 known PD genes per exome were used to calculate average rare variant burden with the 616 non-PD exomes available in-house as a comparison group. SKAT-O test was used for gene level analysis. Results: 80 patients harboured rare variants in 20 PD genes, of which six had known pathogenic variants accounting for 2.4% of the cohort. Of 80 patients, 12 had homozygous and nine had likely compound heterozygous variants in recessive PD genes and 59 had heterozygous variants in only dominant PD genes. Of the 16 novel variants of as yet unknown significance identified, four homozygous across ATP13A2, PRKN, SYNJ1 and PARK7 ; and 12 heterozygous among LRRK2, VPS35, EIF4G1 and CHCHD2 were observed. SKAT-O test suggested a higher burden in GBA ( p unadjusted = 0.002). Aggregate rare variant analysis including 75 more individuals with only heterozygous variants in recessive PD genes (excluding GBA ), with an average of 0.85 protein-altering rare variants per PD patient exome versus 0.51 in the non-PD group, revealed a significant enrichment (p < 0.0001). Conclusion: This first study in an early onset PD cohort among Indians identified 16 novel variants in known genes and also provides evidence for a high genetic burden in this ethnically distinct population. Highlights: WES in an Indian early-onset PD cohort revealed 16 novel variants in known genes. Known pathogenic variants explained 2.4% of the cohort. Evidence for a higher genetic burden in ethnically distinct Indian population. First report of VPS35 p.D620 N mutation from the Indian population. Observations suggest the digenic contribution for PD, warranting further studies.